Process for the preparation of propionic acid derivatives

ABSTRACT

The invention relates to a process for the preparation of a compound of formula (I) 
     
       
         
         
             
             
         
       
     
     or a salt thereof.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.09156074.8, filed Mar. 24, 2009, and of European Patent Application No.09178220.1, filed Dec. 7, 2009, both of which are hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention is concerned with a novel process for thepreparation of(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid or a salt thereof.

The invention relates in particular to a process for the preparation ofa compound of formula (I)

or a salt thereof, wherein a compound of formula (II)

or a salt thereof is hydrogenated(a) in the presence of a catalyst comprising iridium; or(b) in the presence of a catalyst comprising ruthenium and a compoundof: formula (IV),

or formula (VII),

whereinR³ is alkyl, cycloalkyl or aryl;R⁴ is cycloalkyl, aryl or heteroaryl;R⁵ is cycloalkyl or aryl;R⁶ is cycloalkyl or aryl;R⁷ is cycloalkyl or aryl;R⁸ is cycloalkyl or aryl; andR⁹ is cycloalkyl or aryl.

BACKGROUND OF THE INVENTION

The compound of formula (I) is known in the art and is described forexample in international application WO 02/092084. It is especiallyuseful for the prophylaxis and/or treatment of diabetes mellitus type Iand II.

The process according to the invention allows the synthesis of thecompound of formula (I) with high enantiomeric excess. It can beperformed in dichloromethane and the use of complex solvent mixtures canbe avoided. The process with the catalyst comprising iridium givesparticularly high yield and high enantiomeric excess of the compound offormula (I).

Furthermore, optically pure compound of formula (I) is obtained withoutthe use of multiple crystallization of diastereomeric salts.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of acompound of formula (I)

or a salt thereof, wherein a compound of formula (II)

or a salt thereof is hydrogenated(a) in the presence of a catalyst comprising iridium; or(b) in the presence of a catalyst comprising ruthenium and a compoundof: formula (IV),

or formula (VII),

whereinR³ is alkyl, cycloalkyl or aryl;R⁴ is cycloalkyl, aryl or heteroaryl;R⁵ is cycloalkyl or aryl;R⁶ is cycloalkyl or aryl;R⁷ is cycloalkyl or aryl;R⁸ is cycloalkyl or aryl; andR⁹ is cycloalkyl or aryl.

The present invention relates also to a compound of formula (I) or asalt thereof obtained using the above process.

DETAILED DESCRIPTION OF THE INVENTION

The term “catalyst” refers to a complex of ruthenium or iridiumrespectively with a chiral ligand. In such ruthenium complexes,ruthenium is preferably characterised by the oxidation number II. Insuch iridium complexes, iridium is preferably characterized by theoxidation number I.

The term “alkyl” refers to a branched or straight chain monovalent alkylradical of one to eight carbon atoms, preferably one to four carbonatoms. This term is further exemplified by such radicals as methyl,ethyl, n-propyl, iso-propyl, iso-butyl, n-butyl, tert-butyl and the likewith methyl, tert-butyl and iso-propyl being preferred.

The term “alkoxy” refers to the group alkyl-O—. A preferred alkoxy groupis methoxy.

The term “cycloalkyl” refers to a monovalent carbocyclic radical of 3 to10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl. Cyclohexyl is a preferredcycloalkyl.

The term “aryl” relates to the phenyl or naphthyl group, preferably thephenyl group, which can optionally be mono- or multiply-substituted,particularly mono-, di- or tri-substituted by halogen, hydroxy, CN, CF₃,NO₂, NH₂, N(H, alkyl), N(alkyl)₂, carboxy, aminocarbonyl, alkyl, alkoxy,phenyl and/or phenyloxy. Preferred substituents are halogen, alkyl, CF₃and alkoxy, particularly alkyl, CF₃ and alkoxy.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring whichcan comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/orsulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl,isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl. The term “heteroaryl”further refers to bicyclic aromatic groups comprising two 5- or6-membered rings, in which one or both rings can comprise 1, 2 or 3atoms selected from nitrogen, oxygen or sulphur such as e.g. indole orquinoline, or partially hydrogenated bicyclic aromatic groups such ase.g. indolinyl. A heteroaryl group may have a substitution pattern asdescribed earlier in connection with the term “aryl”. Preferredheteroaryl groups are 2-thienyl and 2-furyl. 2-Furyl is particularlypreferred.

The term “halide” refers to a halogen atom bearing a negative chargesuch as fluoride, chloride, bromide and iodide.

The term “pharmaceutically acceptable salts” embraces salts of thecompound of formula (I) with pharmaceutically acceptable bases such asalkali salts, e.g. Na- and K-salts, alkaline earth salts, e.g. Ca- andMg-salts, and ammonium or alkyl-substituted ammonium salts, such as e.g.trimethylammonium salts. A preferred pharmaceutically acceptable salt ofthe compound of formula (I) is the sodium salt.

The term “η⁵” means eta5 as used normally in coordination chemistry. Itindicates the number of electrons shared between a metal center and aligand in a coordination compound or complex.

The present invention relates to a process for the preparation of acompound of formula (I)

or a salt thereof, wherein a compound of formula (II)

or a salt thereof is hydrogenated(c) in the presence of a catalyst comprising iridium; or(d) in the presence of a catalyst comprising ruthenium and a compoundof: formula (IV),

or formula (VII),

whereinR³ is alkyl, cycloalkyl or aryl;R⁴ is cycloalkyl, aryl or heteroaryl;R⁵ is cycloalkyl or aryl;R⁶ is cycloalkyl or aryl;R⁷ is cycloalkyl or aryl;R⁸ is cycloalkyl or aryl; andR⁹ is cycloalkyl or aryl.

A preferred process is process according to the invention wherein thecatalyst comprises iridium and a compound of formula (III),

or formula (IX),

whereinR¹ is hydrogen, alkyl, aryl or arylalkyl;R² is aryl; andR¹⁰ is aryl.

Further preferred is a process according as defined above wherein thecatalyst comprises iridium and a compound of formula (III)

wherein R¹ and R² are as defined above.

Also particularly preferred is a process as defined above wherein thecatalyst comprises iridium and a compound of formula (X)

wherein R¹ and R² are as defined above.R¹ is preferably hydrogen, alkyl, phenyl or benzyl, more preferablyhydrogen, alkyl or benzyl.

In particular, a process as defined above wherein R¹ is hydrogen,iso-propyl, phenyl or benzyl is preferred. More preferably, R¹ ishydrogen, iso-propyl or benzyl.

Also preferred is a process as defined above wherein R² is phenyl orphenyl substituted with one or two alkyl.

Moreover, preferred is a process according to the invention wherein R²is phenyl, 3,5-di-methylphenyl or 3,5-di-tert-butyl-phenyl.

A process according to the invention wherein R¹⁰ is 3,5-di-methyl-phenylis further preferred.

The compound of formula (IX) is(S,R,R)-1,1′-bis-[((1-N,N-dimethylamino)ethylferrocenyl)(phenylphosphino)]ferrocene.

A preferred compound of formula (VIII) is(S,S)-[1,3-dimethyl-1,3-propanediyl]bis[di-(3,5-dimethylphenyl)phosphine].

Particularly preferred is a process according to the invention whereinthe compound of formula (III) is

-   (S_(a),S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1′-spirobiindane;-   (S_(a),S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane;-   (S_(a),S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;-   (S_(a),S)-7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;-   (S_(a),S)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;    or-   (S_(a))-7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.

Further preferred is a process according to the invention wherein thecompound of formula (III) is

-   (S_(a),S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;-   (S_(a),S)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;    or-   (S_(a))-7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.

Still further preferred is a process according to the invention whereinthe compound of formula (X) is(S_(a),R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1′-spirobiindane;

-   (S_(a),R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane;-   (S_(a),R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;-   (S_(a),R)-7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;    or-   (S_(a),R)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.

Moreover, preferred is a process as defined above wherein the catalystis Ir(L¹)(L²)Y wherein

Ir is iridium;L¹ is a compound of formula (III), (VIII) or (IX) as defined above;L² is cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadiene ornorbornadiene;Y is chloride, iodide, bromide, fluoride, trifluoroacetate,tetrafluoroborate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate,tetraphenylborate, hexafluoroantimonate, hexafluorophosphate, triflate,mesylate, perchlorate, perbromate, periodate, nitrate, hydrogen sulfateor acetylacetonate; andn is 1 or 2.

Also preferred is a process as defined above wherein the catalyst isIr(L¹)(L²)Y wherein L¹ is a compound of formula (X) and wherein Ir, L²,Y and n are as defined above.

Particularly preferred is a process wherein L¹ is a compound of formula(III).

Y is preferably chloride, tetrafluoroborate, hexafluorophosphate ortetrakis[3,5-bis(trifluoromethyl)phenyl]borate, more preferablytetrafluoroborate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.

In particular, preferred is a process according to the invention whereinthe catalyst is

-   [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];-   [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrafluoroborate];-   [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][trifluoromethanesulfonate];-   [Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][chloride];-   [Ir((S,S)-7-[4,5-dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];    or-   [Ir((S)-7-[4,5-dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate].

Further particularly preferred is a process according to the inventionwherein the catalyst is

-   [Ir((S_(a),R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];-   [Ir((S_(a),R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrafluoroborate];-   [Ir((S_(a),R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][trifluoromethanesulfonate];    or-   [Ir((S_(a),R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][chloride].

Also preferred is a process as defined above wherein the catalystcomprises ruthenium and a compound of formula (IV), (V), (VI) or (VII).

R³ is preferably alkyl, cyclohexyl, phenyl, alkylphenyl ordialkylphenyl.

In particular, preferred is a process as defined above wherein R³ istert-butyl, cyclohexyl, phenyl, 2-methyl-phenyl or 3,5-di-methyl-phenyl.

Moreover, R⁴ is preferably alkyl, cyclohexyl, phenyl, naphtyl, furyl orphenyl substituted with one to three substituents independently selectedfrom trifluoromethyl, alkyl and alkoxy.

A process according to the invention wherein R⁴ is tert-butyl,cyclohexyl, phenyl, 3,5-di-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 3,5-di-methyl-4-methoxy-phenyl, 1-naphtyl or2-furyl is also preferred.

R⁵ is preferably cyclohexyl, phenyl or phenyl substituted with one tothree substituents independently selected from alkyl and alkoxy.

Furthermore, a process according to the invention wherein R⁵ is phenyl,cyclohexyl, 3,5-di-methyl-4-methoxy-phenyl or 3,5-di-methyl-phenyl isalso preferred.

R⁶ is preferably cyclohexyl, norbornyl, phenyl or phenyl substitutedwith one to three substituents independently selected from alkyl andtrifluoromethyl.

Moreover, preferred is a process as defined above wherein R⁶ is phenyl,cyclohexyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl ornorbornyl.

R⁷ is preferably cyclohexyl, phenyl or phenyl substituted with one tothree substituents independently selected from alkyl, trifluoromethyland alkoxy.

Also preferred is a process according to the invention wherein R⁷ iscyclohexyl, phenyl, 3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl,3,5-di-methyl-4-methoxy-phenyl or 2-methyl-phenyl.

Particularly preferred is a process according to the invention whereinR⁸ is cyclohexyl or phenyl.

A process according to the invention wherein R⁹ is cyclohexyl or phenylis further preferred.

Furthermore, particularly preferred is a process according to theinvention wherein the compound of formula (IV), (V), (VI), (VII) or(VIII) is

-   (S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;-   (S)-1-[(R)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;-   (S)    -1-[(R)-2-(Di-(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert-butyl    phosphine;-   (S)-1-[(R)-2-(Di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine;-   (S)-1-[(R)-2-(Di-2-furylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;-   (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)    ferrocene;-   (αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene;-   (R)-1-Diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl]ferrocene;-   (S)-1-[(S)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethyl    phenyl)phosphine;-   (R)-1-[(R)-2-(2′-Dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine;    or-   (R)-1-[(R)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi-(2-norbornyl)phosphine.

Moreover, further preferred is a process according to the inventionwherein the compound of formula (IV), (V), (VI) or (VII) is

-   (S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;    or-   (S)-1-[(R)-2-(Di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine.

In particular, preferred is a process as defined above wherein thecatalyst is

Ru(L³)(L⁴)(L⁵)_(m)Y_(p)

wherein,Ru is ruthenium;L³ is a compound of formula (IV), (V), (VI) or (VII) as defined above;L⁴ is η⁵-2,4-dimethylpentadienyl, cyclopentadienyl orη⁵-2,3,4-trimethylpenta-dienyl;L⁵ is halide, acetonitrile, diethyl ether, water, acetone,tetrahydrofuran, dioxane, pyridine, imidazole or thiophene;Y is tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrafluoroborate,tetraphenylborate, hexafluoroantimonate, hexafluorophosphate, triflate,mesylate, hydrogen sulfate or perchlorate;m is 0 or 1; andp is 0 or 1.L⁵ is preferably iodine.m is preferably 1. p is preferably 1.

Particularly preferred is a process as defined above wherein thecatalyst is

-   [Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];-   [Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];-   [Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];-   [Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];-   [Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-2-furylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];-   [Ru(η⁵-2,4-dimethylpentadienyl)((αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)ferrocene)    (acetonitrile)][tetrafluoroborate];-   [Ru(η⁵-2,4-dimethylpentadienyl)((αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene)(acetonitrile)][tetrafluoroborate];-   [RuI(η⁵-2,4-dimethylpentadienyl)((R)-1-diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl]ferrocene)];-   [Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(S)-2-(2′-diphenylphosphinophenyl)    ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine)(acetonitrile)][tetrafluoroborate];-   [Ru(η⁵-2,4-dimethylpentadienyl)((R)-1-[(R)-2-(2′-dicyclohexylphosphinophenyl)    ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine)(acetonitrile)][tetrafluoroborate];    or-   [Ru(η⁵-2,4-dimethylpentadienyl)((R)-1-[(R)-2-(2′-diphenylphosphinophenyl)    ferrocenyl]ethyldi-(2-norbornyl)phosphine)(acetonitrile)][tetrafluoroborate].

Further particularly preferred is a process according to the inventionwherein the catalyst is

-   [Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];    or-   [Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine)    (acetonitrile)][tetrafluoroborate].

According to the invention, the compound of formula (II) can behydrogenated under a pressure of hydrogen gas.

When an iridium catalyst is used, the process is preferably carried outat a temperature of 10 to 120° C., more preferably 40 to 100° C.,particularly preferably 60 to 80° C.

When a catalyst comprising iridium is used, the process is preferablycarried out in a solvent selected from alcohols, fluorinated alcohols,tetrahydrofuran, methyl-tetrahydrofuran, dichloromethane, dialkylethers, aromatic solvents such as benzene, toluene, CF₃—C₆H₅, mono- andpoly-fluorinated aromatic solvents and mixtures thereof, more preferredin methanol, tetrahydrofuran, dichloromethane and mixtures thereof, mostpreferably in methanol/tetrahydrofuran 3:2.

When a catalyst comprising iridium is used, the process is preferablycarried out under a hydrogen pressure range of 1 to 200 bar, morepreferably 10 to 100 bar, particularly preferably 40 to 60 bar. When theligand of formula (III) of (S,S) configuration is used, preferred is apressure of 10 bar. When the ligand of formula (III) of (S_(a),R)configuration is used, preferred is a pressure of 30 bar.

When a catalyst comprising iridium is used, the substrate-to-catalystratio (mol/mol) is preferably 10 to 50000, more preferably between 100and 10000, particularly preferably between 1000 and 5000.

When a catalyst comprising ruthenium is used, the process is preferablycarried out at a temperature of 10 to 120° C., more preferably 20 to 80°C., particularly preferably 30 to 50° C.

When a catalyst comprising ruthenium is used, the process is preferablycarried out in a solvent selected from alcohols, tetrahydrofuran,dichloromethane, fluorinated alcohols, methyl-tetrahydrofuran, ethersand mixtures thereof, preferably methanol, tetrahydrofuran,dichloromethane and mixtures thereof, more preferably in a mixturedichloromethane/tetrahydrofuran 1:1 or in dichloromethane andparticularly preferably in dichloromethane.

When a catalyst comprising ruthenium is used, the process is preferablycarried out under a hydrogen pressure of 1 to 200 bar, more preferably10 to 100 bar, particularly preferably 40 to 60 bar.

When a catalyst comprising ruthenium is used, the substrate-to-catalystratio (mol/mol) is preferably 10 to 50000, more preferably 100 to 10000,particularly preferably 1000 to 5000.

The preferred (S) configuration of the compound of formula (I) has beenobtained with the ligands disclosed in the tables in the experimentalpart. Should a chiral ligand or catalyst afford preferentially thecompound of formula (I) with the (R) configuration, it is clear that theligand or catalyst with the opposite configuration should be used inorder to obtain the compound of formula (I) with the (S) configuration.Both enantiomers of the chiral ligands are equally well accessible.

The invention also relates to a compound of formula (I) as defined aboveor a salt thereof obtained by a process according to the invention.

Furthermore, the invention also relates to the use of a catalyst asdefined above for the preparation of a compound of formula (I) asdefined above.

The catalysts for use in the process of the present invention may beprepared by reacting a compound of formula [Ir(L)Cl]₂, [Ir(L)₂]BARF or[Ir(L)₂]BF₄ where L denotes a neutral ligand, e.g. COD with the desiredligand of formula (III), (VIII), (IX) or (X), e.g.(S,S)-3,5-Xyl-Skewphos or (S,R,R)-TRIFER, in an appropriate solvent,such as e.g. dichloromethane or methanol. The catalyst may be used afterisolation or as prepared in situ. The compounds [Ir(COD)Cl]₂ and[Ir⁺(COD)₂]BF₄ are either commercially available, e.g. from StremChemicals Inc., Newburgport, Mass. USA or can be prepared according tomethods known per se, e.g. J. Herde et al., Inorg. Syn. 1974, 18-20 orM. Green et al., J. Chem. Soc. 1971, 2334-2337.

The term “neutral ligand” as used herein denotes a readily exchangeableligand such as an olefin, e.g. ethylene, propylene, cyclooctene,1,5-hexadiene, norbornadiene, 1,5-cyclooctadiene, a nitrile such asacetonitrile or benzonitrile, or also a solvent such as e.g.tetrahydrofuran, toluene etc. Where more than one such ligand ispresent, these can also be different from each other. A preferredneutral ligand is cyclooctadiene.

EXAMPLES Abbreviations

η⁵-2,4-DMP=η⁵-2,4-dimethylpentadienyl,THF=tetrahydrofuran,NCMe=acetonitrile,TFA=trifluoroacetic acid,COD=1,5-cyclooctadiene,BARF=tetrakis[3,5-bis(trifluoromethyl)phenyl]borate,r.t.=room temperature,S/C=substrate-to-catalyst ratio (mol/mol),HPLC=high pressure liquid chromatography,ee=enantiomeric excess=[(S)−(R)]/[(S)+(R)].DBT=DTB=3,5-di-tert.-butylphenylTriflate=trifluoromethanesulfonate

All ferrocenyl-diphosphine ligands are commercially available fromSolvias AG, CH-4002 Basel. The ruthenium complexes are commerciallyavailable from Umicore AG, D-63457 Hanau-Wolfgang or can be preparedaccording to O. Briel et al. in “Catalysis of Organic Reactions”, 2009,203, CRC Press, Boca Raton. The oxazoline-monophosphine ligands (SIPHOXligands) and their corresponding iridium complexes are commerciallyavailable from Nankai University, Tianjin 300071 China or can beprepared according to Q. L. Zhou et al. J. Am. Chem. Soc. 2008, 130,8584. Xyl-Skewphos and 3,5-tBu-MeOBIPHEP are commercially available fromSolvias AG, CH-4002 Basel. TRIFER is commercially available from PhoenixChemicals, 34 Thursby Rod., Bromborough, Wirral CH62, 3PW, UnitedKingdom (UK) or can be prepared according to P. McCormack et al. Angew.Chem. Int. Ed. 2007, 46, 4141-44.

The atom numbering of SIPHOX ligands is shown below:

The asymmetric configuration of the (S_(a),R) SIPHOX ligand is shownbelow:

The (S_(a),S) configuration of the SIPHOX ligand may also be noted(S,S).

Chiral Phosphorus Ligands

Acronyms Chemical Name Ph-Bn-SIPHOX7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1′-spirobiindane Xyl-Bn-SIPHOX7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane DBT-Bn-SIPHOX7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5- di-tert-butylphenyl)phosphino-1,1′- spirobiindane DBT-Ph-SIPHOX7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′- di(3,5-di-tert-butylphenyl)phosphino-1,1′- spirobiindane DBT-iPr-SIPHOX7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5- di-tert-butylphenyl)phosphino-1,1′- spirobiindane DBT-H-SIPHOX7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane TRIFER 1,1′-Bis-[((1-N,N-dimethylamino)ethylferrocenyl)(phenyl- phosphino)]ferrocene Xyl-Skewphos[1,3-Dimethyl-1,3-propanediyl]bis[di-(3,5- dimethylphenyl)phosphine]PPF—PtBu₂ 1-[2-(Diphenylphosphino)ferrocenyl]ethyldi-tert.-butylphosphine Cy₂PF—PtBu₂1-[2-(Dicyclohexylphosphino)ferro- cenyl]ethyldi-tert.-butylphosphine(4-CF₃Ph)₂PF—PtBu₂ 1-[2-(Di-(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert.-butyl phosphine(3,5-Me₂-4-MeOPh)₂PF—PtBu₂ 1-[2-(Di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert.- butylphosphine 2-Fur₂PF—PtBu₂1-[2-(Di-2-furylphosphino)ferrocenyl]ethyldi- tert.-butylphosphineNMe₂—PPh₂-Mandyphos 2,2′-Bis(α-N,N-dimethylaminophe-nylmethyl)-1,1′-bis(diphenylphosphino) ferrocene NMe₂—P(3,5-Me-4-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)- MeOPh)₂-Mandyphos1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)- phosphino]ferrocenePPPhCHNMe₂—F—PP 1-Diphenylphosphino-2-[α-(N,N-dimethylamino)-o-diphenylphosphinophenyl) methyl]ferrocenePPPhFCHCH₃—P(3,5- 1-[2-(2′-Diphenylphosphinophenyl) CF₃Ph)₂ferrocenyl]-ethyldi(bis-3,5-trifluoromethyl phenyl)phosphineCy₂PPhFCHCH₃P(3,5- 1-[2-(2′-Dicyclohexylphosphino CF₃Ph)₂phenyl)ferrocenyl]ethyldi(bis-3,5- trifluoromethylphenyl)phosphinePPPhFCHCH₃—P(Norbornyl)₂ 1-[2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi-(2-norbornyl)phosphine

Synthesis of Iridium Metal Complexes Examples 1a-1h Example 1.aPreparation of [Ir((S,S)-Xyl-Skewphos)(COD)]BF₄

A 25-ml Schlenk tube was charged with 100 mg of (S,S)-Xyl-Skewphos (0.18mmol), 60 mg of [Ir(COD)Cl]₂ (0.09 mmol) and 5 ml of dichloromethane. Tothe formed dark red solution, 35 mg of silver tetrafluoroborate (0.18mmol) was added in two portions and the resulting suspension was stirredfor 2 hours at r.t. The reaction mixture was filtered over dicalitespeedex and the filter cake was washed with 6 ml of dichloromethane. Thecombined filtrates were rotary evaporated to dryness (50° C./5 mbar).The formed crude product was washed with 8 ml of hexane and dried overhigh vacuum to afford 563 mg (85%) of [Ir((S,S)-Xyl-Skewphos)(COD)]BF₄as a red solid. FT-MS: 853.4 m/z [Ir((S,S)-Xyl-Skewphos)(COD)]⁺, ³¹P-NMR(CDC₃): 14.6 ppm (s).

Example 1.b Preparation of [Ir((S,R,R)-Trifer)(COD)]BARF

A 100-ml Schlenk tube was charged with 400 mg of (S,R,R)-TRIFER (0.44mmol), 584 mg of [Ir(COD)₂]BARF (0.46 mmol) and 40 ml of methanol. Theformed orange solution was stirred for 5 hours at r.t. Then, 12 ml ofwater was added and the formed crystals were filtered off. The filtercake was washed with 32 ml of a mixture of methanol/water (4:1) anddried over high vacuum to afford 804 mg (88%) of[Ir((S,R,R)-TRIFER)(COD)]BARF as orange crystals. FT-MS: 1213.2 m/z[Ir((S,R,R)-TRIFER)(COD)]⁺. ³¹P-NMR (CDC₃): 6.2 ppm (s).

Example 1.c Preparation of [Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]BARF

A 25-ml Schlenk tube was charged with 100 mg of (S_(a),R)-DBT-Bn-SIPHOX(0.127 mmol), 168 mg of [Ir(COD)₂]BARF (0.132 mmol) and 10 ml ofmethanol. To the formed yellow solution was stirred for 2 hours at r.t.,then the reaction mixture rotary evaporated to dryness (50° C./5 mbar).The residue was dissolved in 5 ml of methanol. 0.5 ml of water was addedand the formed yellow suspension was stirred for 30 min at r.t. Thecrystals were filtered off, washed with 3.5 ml of MeOH/water (6:1) anddried over high vacuum to afford 189 mg (76%) of[Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]BARF as an orange solid. FT-MS: 1088.5m/z [Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]⁺, ³¹P-NMR (CDC₃): 16.5 ppm (s).

Example 1.d Preparation of [Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]BF₄

A 25-ml Schlenk tube was charged with 56 mg of (S_(a),R)-DBT-Bn-SIPHOX(0.070 mmol), 24 mg of [Ir(COD)Cl]₂ (0.035 mmol) and 5 ml ofdichloromethane. To the formed orange solution, 14 mg of silvertetrafluoroborate (0.071 mmol) was added and the resulting orangesuspension was stirred for 2 hours at r.t. The reaction mixture wasfiltered over dicalite speedex and the filter cake was washed with 9 mlof dichloromethane. The combined filtrates were rotary evaporated todryness (50° C./5 mbar). The formed crude product was washed with 11 mlof hexane and dried over high vacuum to afford 69 mg (83%) of[Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]BF₄ as an orange solid. FT-MS: 1088.5m/z [Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]⁺, ³¹P-NMR (CDC₃): 16.6 ppm (s).

Example 1.e Preparation of [Ir((R_(a),S)-DBT-Bn-SIPHOX)(COD)]OTf

A 25-ml Schlenk tube was charged with 100 mg of (R_(a),S)-DBT-Bn-SIPHOX(0.127 mmol), 44 mg of [Ir(COD)Cl]₂ (0.505 mmol) and 4 ml ofdichloromethane. To the formed orange solution, 34 mg of silvertrifluoromethanesulfonate (0.130 mmol) was added and the resultingorange suspension was stirred for 2 hours at r.t. The reaction mixturewas filtered over dicalite speedex and the filter cake was washed with 6ml of dichloromethane. The combined filtrates were rotary evaporated todryness (50° C./5 mbar). The formed crude product was washed with 11 mlof hexane and dried over high vacuum to afford 134 mg (85%) of[Ir((R_(a),S)-DBT-Bn-SIPHOX)(COD)]OTf as an orange solid. FT-MS: 1088.5m/z [Ir((R_(a),S)-DBT-Bn-SIPHOX)(COD)]⁺, ³¹P-NMR (CDC₃): 16.6 ppm (s).

Example 1.f Preparation of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BF₄

A 25-ml Schlenk tube was charged with 100 mg of (S,S)-DBT-Bn-SIPHOX(0.127 mmol), 43 mg of [Ir(COD)Cl]₂ (0.063 mmol) and 5 ml ofdichloromethane. To the formed orange solution, 26 mg of silvertetrafluoroborate (0.131 mmol) was added and the resulting orangesuspension was stirred for 2 hours at r.t. The reaction mixture wasfiltered over dicalite speedex and the filter cake was washed with 6 mlof dichloromethane. The combined filtrates were rotary evaporated todryness (50° C./5 mbar). The formed crude product was washed with 8 mlof hexane and dried over high vacuum to afford 148 mg (99%) of[Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BF₄ as an orange solid. FT-MS: 1088.5 m/z[Ir((S,S)-DBT-Bn-SIPHOX)(COD)]⁺, ³¹P-NMR (CDC₃): 16.0 ppm (s).

Example 1.g Preparation of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BF₄

A 25-ml Schlenk tube was charged with 200 mg of (S,S)-DBT-Bn-SIPHOX(0.254 mmol), 87 mg of [Ir(COD)Cl]₂ (0.128 mmol) and 5 ml ofdichloromethane. To the formed orange solution, 43 mg of sodiumtetrafluoroborate (0.384 mmol) was added and the resulting orangesuspension was stirred for 5 hours at r.t. The reaction mixture wasfiltered over dicalite speedex and the filter cake was washed with 8 mlof dichloromethane. The combined filtrates were rotary evaporated todryness (50° C./5 mbar). The formed crude product was washed with 11 mlof hexane and dried over high vacuum to afford 259 mg (87%) of[Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BF₄ as an orange solid. FT-MS: 1088.5 m/z[Ir((S,S)-DBT-Bn-SIPHOX)(COD)]⁺, ³¹P-NMR (CDC₃): 16.0 ppm (s).

Example 1.h Preparation of [Ir((R_(a),S)-DBT-Bn-SIPHOX)(COD)]BF₄

A 25-ml Schlenk tube was charged with 40 mg of (R_(a),S)-DBT-Bn-SIPHOX(0.058 mmol), 18 mg of [Ir(COD)Cl]₂ (0.026 mmol) and 4 ml ofdichloromethane. To the formed orange solution, 9 mg of sodiumtetrafluoroborate (0.076 mmol) was added and the resulting orangesuspension was stirred for 3 hours at r.t. The reaction mixture wasfiltered over dicalite speedex and the filter cake was washed with 6 mlof dichloromethane. The combined filtrates were rotary evaporated todryness (50° C./5 mbar). The formed crude product was washed with 11 mlof hexane and dried over high vacuum to afford 51 mg (86%) of[Ir((R_(a),S)-DBT-Bn-SIPHOX)(COD)]BF₄ as an orange solid. FT-MS: 1088.5m/z [Ir((R_(a),S)-DBT-Bn-SIPHOX)(COD)]⁺, ³¹P-NMR (CDC₃): 16.6 ppm (s).

Synthesis of2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid via asymmetric hydrogenation of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid Examples 2-19 & Comparative Example A Example 2.1

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 35.9 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.018mmol, S/C 250), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 mlof (S)-1-phenylethylamine (0.93 mmol). The autoclave was sealed and thehydrogenation was run at 60° C. under 30 bar of hydrogen. After 16 h theautoclave was opened and the yellowish solution was rotary evaporated todryness (50° C./5 mbar) to afford crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.6% (>99.9%conversion) and an enantiomeric purity of 99.5%.

HPLC method for chemical purity (area-%, (S)-phenylethylamine notincluded): YMC-Pack Pro C18, 150×4.6 mm; mobile phase A: mobile phase A:water with 0.1% TFA, B: NCMe with 0.1% TFA, 22° C., 2 ml/min, isocraticA/B 51/49% during 10 min, gradient from 51/49% to 5/95% within 10 minand 5 min at 5/95%, 285 nm. Retention times: 11.2 min (S)- and(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid; 12.4 min(E)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid; 14.0 min(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid.

HPLC method for ee determination (area-%): Chiralpak-ADH column, 25cm×4.6 mm, 85% heptane/10% ethanol with 0.4% trifluoroacetic acid, flow0.7 ml/min, 30° C., 270 nm. Retention times: 22.4 min(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid; 26.3 min(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid.

Example 2.2

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 2.70 mg of [Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]BF₄(0.0023 mmol, S/C 2′000), 24 ml of methanol, 16 ml of tetrahydrofuranand 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave wassealed and the hydrogenation was run under 30 bar of hydrogen at 60° C.for 20 h and subsequently at 80° C. for 2 h. Then the autoclave wasopened and the yellowish solution was rotary evaporated to dryness (50°C./5 mbar) to afford crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 89.9% (>99.9%conversion) and an enantiomeric purity of 99.8%. The crude product wasdissolved in 50 ml of ethyl acetate. 10 ml of water and 3 ml of 2Maqueous HCl were added and the biphasic mixture was stirred at 55° C.for 15 min. The organic layer was separated, the aqueous layer extractedwith 20 ml of ethyl acetate and the combined organic layers stirred over0.5 g of carcoal (Darko KB) at r.t. for 2 h. After filtration overcelite, the colorless solution was dried over 3 g of sodium sulfate andevaporated to dryness (40° C./10 mbar). The crude product was dissolvedin 50 ml of isopropyl acetate at reflux (oil bath temp. 100° C.) andallowed to cool to room temperature whereby crystallization startedspontaneously. The formed crystals were filtered off, washed with 10 mlof isopropyl acetate and dried at 75° C./500 mbar for 4 h to yield 1.60g (79%) of pure(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white crystals with a chemical purity of 99.6% and anenantiomeric purity of 99.8% ee.

Examples 3.1-3.4

In an analogous manner to Example 2 the following hydrogenations wereperformed at 60° C. under 30 bar of hydrogen (reaction time: 16 h) usingiridium complexes of general formula [Ir(Phosphorous Ligand)(COD)]BARFas catalysts to afford crude2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as listed in Table 1.

TABLE 1 Acid I Ee [%]/ Exp. Conv. Acid I Config- No. Phosphorus Ligand[%] Purity [%] uration 3.1 (S,S)-Xyl-Bn-SIPHOX 99.8 97.6 88.9/S 3.2(S,S)-DBT-Ph-SIPHOX 99.9 99.4 98.0/S 3.3 (S,S)-DBT-iPr-SIPHOX >99.9 99.399.3/S 3.4 (S)-DBT-H-SIPHOX >99.9 98.3 99.3/S

Example 4

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 8.96 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.0046mmol, S/C 1′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12ml of (S)-1-phenylethylamine (0.93 mmol). The autoclave was sealed andthe hydrogenation was run at 60° C. under 30 bar of hydrogen. After 16 hthe autoclave was opened and the yellowish solution was rotaryevaporated to dryness (50° C./5 mbar) to afford the crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.2% (99.8%conversion) and an enantiomeric purity of 99.3%.

Examples 5.1-5.2

In an analogous manner to Example 4 the following hydrogenations wereperformed at 60° C. under 30 bar of hydrogen (reaction time: 16 h) usingiridium complexes of general formula [Ir(Phosphorus Ligand)(COD)]BARF ascatalysts to afford crude2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as listed in Table 2.

TABLE 2 Acid I Ee [%]/ Exp. Conv. Acid I Config- No. Phosphorus Ligand[%] Purity [%] uration 5.1 (S,S)-DBT-iPr-SIPHOX 99.9 99.5 98.7/S 5.2(S)-DBT-H-SIPHOX 99.9 98.1 99.3/S

Example 6.1

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 4.48 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.0023mmol, S/C 2′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12ml of (S)-1-phenylethylamine (0.93 mmol). The autoclave was sealed andthe hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for2 h under 30 bar of hydrogen. After the autoclave was opened and theyellowish solution was rotary evaporated to dryness (50° C./5 mbar) toafford crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.2% (>99.9%conversion) and an enantiomeric purity of 99.4%.

Example 6.2

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 4.48 mg of [Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]BARF(0.0023 mmol, S/C 2′000), 24 ml of methanol, 16 ml of tetrahydrofuranand 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave wassealed and the hydrogenation was run under 30 bar of hydrogen at 60° C.for 20 h and subsequently at 80° C. for 2 h. Then the autoclave wasopened and the yellowish solution was rotary evaporated to dryness (50°C./5 mbar) to afford crude(5)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.0% (>99.9%conversion) and an enantiomeric purity of 99.8%.

Example 7

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 8.96 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.0046mmol, S/C 1′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12ml of (S)-1-phenylethylamine (0.93 mmol). The autoclave was sealed andthe hydrogenation was run at 60° C. for 8 h and subsequently 80° C. for2 h under 30 bar of hydrogen. After the autoclave was opened and theyellowish solution was rotary evaporated to dryness (50° C./5 mbar) toafford 2.24 g of the crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.2% (>99.9%conversion) and an enantiomeric purity of 99.2%. The crude product wasdissolved in 50 ml of ethyl acetate. 10 ml of water and 3 ml of 2Maqueous HCl were added and the biphasic mixture was stirred at 55° C.for 15 min. The organic layer was separated, the aqueous layer extractedwith 20 ml of ethyl acetate and the combined organic layers stirred over0.5 g of carcoal (Darko KB) at r.t. for 30 min. After filtration overcelite, the colorless solution was dried over 3 g of sodium sulfate andevaporated to dryness (40° C./10 mbar). The crude product was dissolvedin 50 ml of isopropyl acetate at reflux (oil bath temp. 100° C.) andallowed to cool to room temperature whereby crystallization startedspontaneously. The formed crystals were filtered off, washed with 10 mlof isopropyl acetate and dried at 60° C./10 mbar for 2 h to yield 1.40 g(70%) of pure(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white crystals with a chemical purity of 99.8% and anenantiomeric purity of >99.9% ee.

Example 8.1

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 4.48 mg of [Ir((S,S)-DBT-Bn-SIPHOX)(COD)]BARF (0.0023mmol, S/C 2′000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12ml of (S)-1-phenylethylamine (0.93 mmol). The autoclave was sealed andthe hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for2 h under 10 bar of hydrogen. After the autoclave was opened and theyellowish solution was rotary evaporated to dryness (50° C./5 mbar) toafford crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 98.9% (>99.9%conversion) and an enantiomeric purity of 99.6%.

Example 8.2

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 5.40 mg of [Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]BF₄(0.0046 mmol, S/C 1′000), 24 ml of methanol, 16 ml of tetrahydrofuranand 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave wassealed and the hydrogenation was run at 60° C. for 20 h and subsequently80° C. for 2 h under 10 bar of hydrogen. After the autoclave was openedand the yellowish solution was rotary evaporated to dryness (50° C./5mbar) to afford crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 89.7% (91.1%conversion) and an enantiomeric purity of 99.8%.

Example 8.3

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 2.84 mg of [Ir((R_(a),S)-DBT-Bn-SIPHOX)(COD)]OTf(0.0023 mmol, S/C 2′000), 24 ml of methanol, 16 ml of tetrahydrofuranand 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave wassealed and the hydrogenation was run at 60° C. for 20 h and subsequently80° C. for 2 h under 30 bar of hydrogen. After the autoclave was openedand the yellowish solution was rotary evaporated to dryness (50° C./5mbar) to afford crude(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 98.7% (99.7%conversion) and an enantiomeric purity of 99.8%.

Example 8.4

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 1.80 mg of [Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]BF₄(0.0015 mmol, S/C 3′000), 24 ml of methanol, 16 ml of tetrahydrofuranand 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave wassealed and the hydrogenation was run at 60° C. for 20 h and subsequently80° C. for 2 h under 60 bar of hydrogen. After the autoclave was openedand the yellowish solution was rotary evaporated to dryness (50° C./5mbar) to afford crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 98.3% (99.4%conversion) and an enantiomeric purity of 99.7%.

Example 8.5

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 0.77 mg of [Ir(COD)Cl]₂ (0.0012 mmol, S/C 2′000), 1.81mg of (R_(a),S)-DBT-Bn-SIPHOX (0.0023 mmol) and 10 ml oftetrahydrofuran. The formed yellow solution was stirred for 30 min atambient temperature. Then, 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 24 ml of methanol, 6 ml of tetrahydrofuran and 0.12 mlof (S)-1-phenylethylamine (0.92 mmol) were added. The autoclave wassealed and the hydrogenation was run at 60° C. for 20 h and subsequently80° C. for 2 h under 30 bar of hydrogen. After the autoclave was openedand the yellowish solution was rotary evaporated to dryness (50° C./5mbar) to afford crude(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 98.5% (>99.9%conversion) and an enantiomeric purity of 99.5%.

Example 8.6

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 1.14 mg of [Ir(COD)₂]BF₄ (0.0023 mmol, S/C 2′000), 1.99mg of (R_(a),S)-DBT-Bn-SIPHOX (0.0025 mmol) and 10 ml oftetrahydrofuran. The formed yellow solution was stirred for 30 min atambient temperature. Then, 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (4.59 mmol), 24 ml of methanol, 6 ml of tetrahydrofuran and 0.12 mlof (S)-1-phenylethylamine (0.92 mmol) were added. The autoclave wassealed and the hydrogenation was run at 60° C. for 20 h and subsequently80° C. for 2 h under 30 bar of hydrogen. After the autoclave was openedand the yellowish solution was rotary evaporated to dryness (50° C./5mbar) to afford crude(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 98.7% (>99.9%conversion) and an enantiomeric purity of 99.6%.

Example 8.7

In a glove box (O₂ content ≦2 ppm), a 185-ml stainless steel autoclavewas charged with 2.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[ID]thiophen-7-yl}-acrylic acid (4.59 mmol), 1.80 mg of[Ir((S_(a),R)-DBT-Bn-SIPHOX)(COD)]BF₄ (0.0015 mmol, S/C 3′000), 24 ml ofmethanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine(0.92 mmol). The autoclave was sealed and the hydrogenation was run at80° C. for 22 h under 30 bar of hydrogen. After the autoclave was openedand the yellowish solution was rotary evaporated evaporated to dryness(50° C./5 mbar) to afford crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 96.7% (99.9%conversion) and an enantiomeric purity of 99.5%.

Example 9

In an analogous manner to Example 4 the following hydrogenation wasperformed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) using[Ir((S,S)-Xyl-Skewphos)(COD)]BF₄ (S/C 1′000) as catalysts to affordcrude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 98.8% (99.4%conversion) and an enantiomeric purity of 85%.

Example 10

In an analogous manner to Example 2 the following hydrogenation wasperformed at 60° C. under 30 bar of hydrogen (reaction time: 16 h) using[Ir((S,R,R)-Trifer)(COD)]BARF (S/C 250) as catalysts to afford crude(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 98.0% (>99.9%conversion) and an enantiomeric purity of 86%.

Example 11

In a glove box (O₂ content ≦2 ppm), a 50-ml stainless steel autoclavewas charged with 1.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (2.30 mmol),1.99 mg of [Ru(η⁵-2,4-DMP)((R)—(S)-PPF—PtBu₂)(NCMe)]BF₄(0.0023 mmol, S/C 1′000), 12 ml of methanol, 8 ml of dichloromethane and0.06 ml of (S)-1-phenylethylamine (0.47 mmol). The autoclave was sealedand the hydrogenation was run at 40° C. under 30 bar of hydrogen. After16 h the autoclave was opened and the yellowish solution was rotaryevaporated to dryness (50° C./5 mbar) to afford the crude(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.6% (>99.9%conversion) and an enantiomeric purity of 89%.

HPLC method for chemical purity (area-%, (S)-phenylethylamine notincluded): YMC-Pack Pro C18, 150×4.6 mm; mobile phase A: mobile phase A:water with 0.1% TFA, B: NCMe with 0.1% TFA, 22° C., 2 ml/min, isocraticA/B 51/49% during 10 min, gradient from 51/49% to 5/95% within 10 minand 5 min at 5/95%, 285 nm. Retention times: 11.2 min (S)- and(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid; 12.4 min(E)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid; 14.0 min(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid.

HPLC method for ee determination (area-%): Chiralpak-ADH column, 25cm×4.6 mm, 90% heptane/10% ethanol with 0.5% trifluoroacetic acid, flow0.7 ml/min, 30° C., 270 nm. Retention times: 22.1 min(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid; 26.0 min(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid.

Examples 12.1-12.5

In an analogous manner to Example 11 the following hydrogenations wereperformed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) usingruthenium complexes of general formula [Ru(η⁵-2,4-DMP)(PhosphorousLigand)(NCMe)]BF₄ as catalysts to afford crude2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as listed in Table 3.

TABLE 3 Acid I Ee [%]/ Exp. Conv. Acid I Config- No. Phosphorus Ligand[%] Purity [%] uration 12.1 (R)-(R)-PPPhFCHCH₃— >99.9 97.1 69/SP(Norbornyl)₂ 12.2 (R)-(R)-Cy₂PPhFCH— >99.9 99.4 79/S CH₃P(3,5-CF₃Ph)₂12.3 (R)-(S)-NMe₂—PPh₂- 99.6 99.1 69/S Mandyphos 12.4(R)-(S)-NMe₂—P(3,5-Me-4- 99.3 98.8 70/S MeOPh)₂-Mandyphos 12.5(R)-(R)-PPPhFCHCH₃— >99.9 99.6 58/R P(3,5-CF₃Ph)₂

Example 13

In an analogous manner to Example 11 the following hydrogenations wereperformed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) usingruthenium complex [RuI(η⁵-2,4-DMP)((S)—(R)—PPPhCHNMe₂F—PP)] as catalyststo afford crude(S)-2-methoxy-3-{1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 98.7% (99.2%conversion) and an enantiomeric purity of 46%.

Example 14

In a glove box (O₂ content ≦2 ppm), a 50-ml stainless steel autoclavewas charged with 2.26 mg of[Ru(η⁵-2,4-DMP)((S)—(R)-(3,5-Me₂-4-MeOPh)₂PF—PtBu₂)(NCMe)]BF₄ (0.0023mmol, S/C 1′000) and 6 ml of dichloromethane. The resulting violetsolution was stirred for 2 h at r.t. Then, 1.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (2.30 mmol), 4 ml of dichloromethane, 10 ml of THF and 0.06 ml of(S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealedand the hydrogenation was run under stirring at 40° C. under 30 bar ofhydrogen. After 16 h the autoclave was opened and the yellowish solutionwas rotary evaporated to dryness (50° C./5 mbar) to afford the crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.5% (>99.9%conversion) and an enantiomeric purity of 87%.

Example 15

In an analogous manner to Example 14 the following hydrogenations wereperformed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) usingruthenium complex [Ru(5-2,4-DMP)((S)—(R)-2-Fur2PF—PtBu2)(NCMe)]BF4 ascatalysts to afford crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.3% (>99.9%conversion) and an enantiomeric purity of 73%.

Example 16

In a glove box (O₂ content ≦2 ppm), a 50-ml stainless steel autoclavewas charged with 1.99 mg of [Ru(η⁵-2,4-DMP)((R)—(S)—PPF—PtBu₂)(NCMe)]BF₄(0.0023 mmol, S/C 1′000) and 5 ml of dichloromethane. The resultingviolet solution was stirred for 2 h at r.t. Then, 1.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (2.30 mmol), 2.5 ml of dichloromethane, 7.5 ml of THF and 0.06 mlof (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave wassealed and the hydrogenation was run under stirring at 40° C. under 30bar of hydrogen. After 16 h the autoclave was opened and the yellowishsolution was rotary evaporated to dryness (50° C./5 mbar) to afford(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.2% (>99.9%conversion) and an enantiomeric purity of 90%.

Examples 17.1-17.2

In an analogous manner to Example 16 the following hydrogenations wereperformed at 40° C. under 30 bar of hydrogen (reaction time: 16 h) usingruthenium complexes of general formula [Ru(η⁵-2,4-DMP)(PhosphorusLigand)(NCMe)]BF₄ as catalysts to afford crude2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as listed in Table 4.

TABLE 4 Acid I Ee [%]/ Exp. Conv. Acid I Config- No. Phosphorus Ligand[%] Purity [%] uration 17.1 (S)-(R)-Cy₂PF—PtBu₂ 98.7 98.6 74/S 17.2(S)-(R)-(4-CF₃Ph)₂PF— 99.9 99.6 84/S PtBu₂

Example 18

In a glove box (O₂ content ≦2 ppm), a 50-ml stainless steel autoclavewas charged with 0.66 mg of [Ru(η⁵-2,4-DMP)((R)—(S)—PPF—PtBu₂)(NCMe)]BF₄(0.0008 mmol, S/C 3′000) and 5 ml of dichloromethane. The resultingviolet solution was stirred for 2 h at r.t. Then, 1.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (2.30 mmol), 2.5 ml of dichloromethane, 7.5 ml of THF and 0.06 mlof (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave wassealed and the hydrogenation was run under stirring at 40° C. under 30bar of hydrogen. After 16 h the autoclave was opened and the yellowishsolution was rotary evaporated to dryness (50° C./5 mbar) to afford(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.5% (99.9%conversion) and an enantiomeric purity of 89%.

Example 19

In a glove box (O₂ content ≦2 ppm), a 50-ml stainless steel autoclavewas charged with 0.66 mg of [Ru(η⁵-2,4-DMP)((R)—(S)—PPF—PtBu₂)(NCMe)]BF₄(0.0008 mmol, S/C 3′000) and 5 ml of dichloromethane. The resultingviolet solution was stirred for 2 h at r.t. Then, 1.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (2.30 mmol), 10 ml of dichloromethane and 0.06 ml of(S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealedand the hydrogenation was run under stirring at 40° C. under 30 bar ofhydrogen. After 16 h the autoclave was opened and the yellowish solutionwas rotary evaporated to dryness (50° C./5 mbar) to afford(R)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.5% (99.9%conversion) and an enantiomeric purity of 90%.

Comparative Example A

In a glove box (O₂ content ≦2 ppm), a 50-ml stainless steel autoclavewas charged with 0.62 mg of [Ru(OAc)₂((S)-TMBTP)] (0.0008 mmol, S/C3′000) (prepared according to EP 1,670,792 B1;TMBTP=2,2′,5,5′-Tetramethyl-4,4′-bis(diphenylphosphino)-3,3′-bithiophene)and 5 ml of methanol. The resulting orange solution was stirred for 2 hat r.t. Then, 1.00 g of(Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylicacid (2.30 mmol), 4 ml of methanol, 6 ml of THF and 0.06 ml of(S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealedand the hydrogenation was run under stirring at 40° C. under 30 bar ofhydrogen. After 16 h the autoclave was opened and the yellowish solutionwas rotary evaporated to dryness (50° C./5 mbar) to afford crude(S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionicacid (Acid I) as a white solid with a chemical purity of 99.7% (99.9%conversion) and an enantiomeric purity of 89%.

1. A process for the preparation of a compound of formula (I)

or a salt thereof, wherein a compound of formula (II)

or a salt thereof is hydrogenated (e) in the presence of a catalystcomprising iridium; or (f) in the presence of a catalyst comprisingruthenium and a compound of: formula (IV),

or formula (VII),

wherein R³ is alkyl, cycloalkyl or aryl; R⁴ is cycloalkyl, aryl orheteroaryl; R⁵ is cycloalkyl or aryl; R⁶ is cycloalkyl or aryl; R⁷ iscycloalkyl or aryl; R⁸ is cycloalkyl or aryl; and R⁹ is cycloalkyl oraryl.
 2. A process according to claim 1, wherein the catalyst comprisesiridium and a compound of formula (III),

or formula (IX),

wherein R¹ is selected from the group consisting of: hydrogen, alkyl,aryl and arylalkyl; R² is aryl; and R¹⁰ is aryl.
 3. A process accordingto claim 2, wherein the catalyst comprises iridium and a compound offormula (III)


4. A process according to claim 1, wherein the catalyst comprisesiridium and a compound of formula (X)

wherein: R¹ is selected from the group consisting of: hydrogen, alkyl,aryl and arylalkyl; and R² is aryl.
 5. A process according to claim 2,wherein R¹ is selected from the group consisting of: hydrogen,iso-propyl, phenyl and benzyl.
 6. A process according to claim 2,wherein R² is selected from the group consisting of: phenyl,3,5-di-methylphenyl and 3,5-di-tert-butyl-phenyl.
 7. A process accordingto claim 2, wherein R¹⁰ is 3,5-di-methyl-phenyl.
 8. A process accordingto claim 2, wherein the compound of formula (III) is selected from thegroup consisting of:(S_(a),S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1′-spirobiindane;(S_(a),S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane;(S_(a),S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;(S_(a),S)-7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;(S_(a),S)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;and(S_(a))-7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.9. A process according to claim 2, wherein the compound of formula (III)is selected from the group consisting of:(S_(a),S)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;(S_(a),S)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;and(S_(a))-7-[4,5-Dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.10. A process according to claim 4, wherein the compound of formula (X)is selected from the group consisting of:(S_(a),R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-diphenylphosphino-1,1′-spirobiindane;(S_(a),R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-methylphenyl)phosphino-1,1′-spirobiindane;(S_(a),R)-7-[4,5-Dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;(S_(a),R)-7-[4,5-Dihydro-4-phenyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane;and(S_(a),R)-7-[4,5-Dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane.11. A process according to claim 2, wherein the catalyst is Ir(L¹)(L²)Ywherein: Ir is iridium; L′ is a compound of formula (III), (VIII) or(IX); L² is selected from the group consisting of: cyclooctene,1,5-cyclooctadiene, ethylene, 1,5-hexadiene and norbornadiene; Y isselected from the group consisting of: chloride, iodide, bromide,fluoride, trifluoroacetate, tetrafluoroborate,tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetraphenylborate,hexafluoroantimonate, hexafluorophosphate, triflate, mesylate,perchlorate, perbromate, periodate, nitrate, hydrogen sulfate andacetylacetonate; and n is 1 or
 2. 12. A process according to claim 4wherein the catalyst is Ir(L¹)(L²)Y wherein: Ir is iridium; L′ is acompound of formula (X); L² is selected from the group consisting of:cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadiene andnorbornadiene; Y is selected from the group consisting of: chloride,iodide, bromide, fluoride, trifluoroacetate, tetrafluoroborate,tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetraphenylborate,hexafluoroantimonate, hexafluorophosphate, triflate, mesylate,perchlorate, perbromate, periodate, nitrate, hydrogen sulfate andacetylacetonate; and n is 1 or
 2. 13. A process according to claim 1,wherein the catalyst is selected from the group consisting of:[Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];[Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrafluoroborate];[Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][trifluoromethanesulfonate];[Ir((S,S)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][chloride];[Ir((S,S)-7-[4,5-dihydro-4-isopropyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];and[Ir((S)-7-[4,5-dihydrooxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate].14. A process according to claim 12, wherein the catalyst is selectedfrom the group consisting of:[Ir((S_(a),R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrakis[3,5-bis(trifluoromethyl)phenyl]borate];[Ir((S_(a),R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][tetrafluoroborate];[Ir((S_(a),R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][trifluoromethanesulfonate];and[Ir((S_(a),R)-7-[4,5-dihydro-4-benzyloxazol-2-yl]-7′-di(3,5-di-tert-butylphenyl)phosphino-1,1′-spirobiindane)(1,5-cyclooctadiene)][chloride].15. A process according to claim 1, wherein the catalyst comprisesruthenium and a compound of formula (IV), (V), (VI) or (VII).
 16. Aprocess according to claim 1, wherein R³ is selected from the groupconsisting of: tert-butyl, cyclohexyl, phenyl, 2-methyl-phenyl and3,5-di-methyl-phenyl.
 17. A process according to claim 1, wherein R⁴ isselected from the group consisting of: tert-butyl, cyclohexyl, phenyl,3,5-di-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl,3,5-di-methyl-4-methoxy-phenyl, 1-naphtyl and 2-furyl.
 18. A processaccording to claim 1, wherein R⁵ is selected from the group consistingof: phenyl, cyclohexyl, 3,5-di-methyl-4-methoxy-phenyl and3,5-di-methyl-phenyl.
 19. A process according to claim 1, wherein R⁶ isselected from the group consisting of: phenyl, cyclohexyl,3,5-di-methyl-phenyl, 3,5-di-trifluoromethyl-phenyl and norbornyl.
 20. Aprocess according to claim 1, wherein R⁷ is selected from the groupconsisting of: cyclohexyl, phenyl, 3,5-di-methyl-phenyl,3,5-di-trifluoromethyl-phenyl, 3,5-di-methyl-4-methoxy-phenyl and2-methyl-phenyl.
 21. A process according to claim 1, wherein R⁸ iscyclohexyl or phenyl.
 22. A process according to claim 1, wherein R⁹ iscyclohexyl or phenyl.
 23. A process according to claim 1, wherein thecompound of formula (IV), (V), (VI) or (VII) is selected from the groupconsisting of:(S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;(S)-1-[(R)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;(S)-1-[(R)-2-(Di-(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine;(S)-1-[(R)-2-(Di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine;(S)-1-[(R)-2-(Di-2-furylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;(αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)ferrocene;(αR,αR)-2,2′-Bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene;(R)-1-Diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl]ferrocene;(S)-1-[(S)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine;(R)-1-[(R)-2-(2′-Dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine;and(R)-1-[(R)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi-(2-norbornyl)phosphine.24. A process according to claim 1, wherein the compound of formula(IV), (V), (VI) or (VII) is(S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine;or(S)-1-[(R)-2-(Di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine.25. A process according to claim 1, wherein the catalyst isRu(L³)(L⁴)(L⁵)_(m)Y_(p) wherein: Ru is ruthenium; L³ is a compound offormula (IV), (V), (VI) or (VII); L⁴ is η⁵-2,4-dimethylpentadienyl,cyclopentadienyl or η⁵-2,3,4-trimethylpenta-dienyl; L⁵ is selected fromthe group consisting of: halide, acetonitrile, diethyl ether, water,acetone, tetrahydrofuran, dioxane, pyridine, imidazole and thiophene; Yis selected from the group consisting of:tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, hexafluoroantimonate,hexafluorophosphate, triflate, mesylate, hydrogen sulfate andperchlorate; m is 0 or 1; and p is 0 or
 1. 26. A process according toclaim 1, wherein the catalyst is selected from the group consisting of:[Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];[Ru(rη⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];[Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];[Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];[Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-2-furylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];[Ru(η⁵-2,4-dimethylpentadienyl)((αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)ferrocene)(acetonitrile)][tetrafluoroborate];[Ru(η⁵-2,4-dimethylpentadienyl)((αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene)(acetonitrile)][tetrafluoroborate];[RuI(η⁵-2,4-dimethylpentadienyl)((R)-1-diphenylphosphino-2-[(S)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl]ferrocene)];[Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(S)-2-(2′-diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine)(acetonitrile)][tetrafluoroborate];[Ru(η⁵-2,4-dimethylpentadienyl)((R)-1-[(R)-2-(2′-dicyclohexylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine)(acetonitrile)][tetrafluoroborate]; and[Ru(η⁵-2,4-dimethylpentadienyl)((R)-1-[(R)-2-(2′-diphenylphosphinophenyl)ferrocenyl]ethyldi-(2-norbornyl)phosphine)(acetonitrile)][tetrafluoroborate].
 27. A process according to claim 1,wherein the catalyst is[Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate];or[Ru(η⁵-2,4-dimethylpentadienyl)((S)-1-[(R)-2-(di-(3,5-dimethyl-4-methoxyphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine)(acetonitrile)][tetrafluoroborate].28. A compound of formula (I) as defined in claim 1 or a salt thereofobtained by a process according to claim
 1. 29. A process according toclaim 4, wherein R¹ is selected from the group consisting of: hydrogen,iso-propyl, phenyl and benzyl.
 30. A process according to any one ofclaim 4, wherein R² is selected from the group consisting of: phenyl,3,5-di-methylphenyl and 3,5-di-tert-butyl-phenyl.